Clonal evolution (CE) may be a marker of disease progression in chronic myelogenous leukemia (CML) and is thought to reflect the genetic instability of the highly proliferative CML progenitors. The frequency of CE increases with advancing stage, rising from 30%in accelerated phase and up to 80% in blast crisis. Given its association with disease progression, CE is considered a feature that defines accelerated-phase CML; however, not all studies have demonstrated a uniformly poor outcome for patients with CE. Chromosomal abnormalities in Ph chromosome negative metaphases increasingly have been recognized in patients treated with imatinib. The true incidence of this phenomenon is not clear but appears to occur in 2% to 17% of imatinib-treated patients. Regardless of the precise mechanism and the long-term clinical implications, the findings described in this article underscore the importance of routine cytogenetic analysis for patients treated with imatinib. The continued study of these phenomena will help us to understand better the pathogenesis of CML and improve the long-term treatment of patients with CML.